Migrating Cancer Cells Follow Their Noses into Body Tissues

Migrating cancer cells could use a nose job – not for appearances’ sake, but to cut down on metastasis. A pronounced nose, which indicates a high degree of polarization, isn’t found on every cancer cell that breaks free of a tumor and enters the circulatory system. But the more polarized cancer cells do seem to be better at invading tissues and settling at body sites, some of which may be far from the primary tumor.

The ability of circulating cancer cells to nose into body tissues has been investigated by scientists based at the German Cancer Research Center (DKFZ). According to these scientists, metastatic potential correlates with degree of polarization, the extent to which a cell organizes its structural components to support an asymmetric pose.

Measurements of polarization, the scientists propose, could help clinicians predict metastasis in cancer patients. Also, polarization-reducing drugs could help prevent metastasis.

Polarization, it is well known, characterizes cells that dedifferentiate and migrate during development. What’s new, however, is the finding that polarity may be maintained by metastasizing tumor cells during phases of detachment. Consequently, the polarization of circulating cancer cells, not just their number, should factor into assessments of metastatic risk.

Detailed findings uncovered by the DKFZ-led scientific team appeared February 28 in the journal Nature Communications, in an article entitled “Single Cell Polarity in Liquid Phase Facilitates Tumour Metastasis.” The article notes that in human cancer cells as well as in patients with different types of cancer, and also in mice, the scientists observed that a portion of the circulating cancer cells exhibit a specific polarity.

“…we identify and characterise a type of polarisation maintained by single cells in liquid phase termed single-cell (sc) polarity and investigate its role during metastasis,” the article’s authors wrote. “We demonstrate that sc polarity is an inherent feature of cells from different tumour entities that is observed in circulating tumour cells in patients.”

Two cytoskeletal proteins called ezrin and merlin play a key role in sc polarity. “Under the microscope, this looks as if the cells had a kind of nose,” said the DKFZ’s Mathias Heikenwälder, Ph.D.

“This polarity seems to help the free cancer cells return from the blood vessels into body tissue,” explained Anna Lorentzen, who is the first author of the publication and a researcher affiliated with Helmholtz Center Munich and Aarhus University. With the polarized end, that is, with the nose, the cells attach to the endothelial layer lining the interior of the vessels. Subsequently, the pole is shifted to the side facing the attachment site and the tumor cell migrates through the endothelial layer into the tissue.

As a cross-check, the researchers used a cell-biological trick to block polarization of the circulating cells. Both in culture and in mice, the manipulated cells were no longer able to attach efficiently to endothelial cells.

“In vivo, the metastatic capacity of cell lines correlates with the extent of sc polarisation,” the authors of the Nature Communications article indicated. “By manipulating sc polarity regulators and by generic depolarisation, we show that sc polarity prior to migration affects transmigration and metastasis in vitro and in vivo.”

With this discovery, the DKFZ researchers and their colleagues have not only found a new mechanism promoting the formation of metastatic sites; they have “also have found a link that might in future be used to better predict and even reduce the risk for metastasis in cancer patients,” Heikenwälder stressed.